The present invention relates generally to the synthesis of imine intermediates which are useful in preparing aldehydes and unsymmetrical secondary amines, and also to the synthesis of unsymmetrical secondary amines. Specifically, the present invention relates to the preparation of stable imines by hydrogenating a mixture of a pyridinecarbonitrile and a primary amine in the presence of hydrogen and a rhodium-loaded hydrogenation catalyst, and the subsequent use of these imines as precursors of aldehydes and secondary amines. Further, the present invention specifically relates to the preparation of unsymmetrical secondary amines of the general formula RCH.sub.2 NHAr, wherein R is non-aliphatic and Ar is aromatic, by reductively coupling a nitrile of the formula RCN and a primary aromatic amine.
Although the presence of imine intermediates in nitrile hydrogenations has been proposed and imines are suspected by-products from the hydrogenation of nitriles in the presence of primary amines, commercially useful quantities of selected imine products, as well as isolation or characterization of the same, from the hydrogenation of a pyridinecarbonitrile and a primary amine has been unknown. Rylander, P. N. and Hasbrouck, L., Eng. Tech. Bull., 11, 19 (1970), identified (by infrared) small quantities of uncharacterized imine as some unspecified portion of the miscellaneous compounds formed upon hydrogenation of benzonitrile and butylamine to produce high yields of various amines. No miscellaneous compounds were reported when a rhodium catalyst was used. Moreover, the Rylander and Hasbrouck work suggests that amine products are nearly quantitatively favored when nitrile hydrogenations take place in the presence of amines. In contrast, Applicants have discovered that pyridinecarbonitriles hydrogenated in the presence of rhodium and a primary amine unexpectedly form imines in good yield.
Imines have also been proposed as intermediates to explain the alkyl group exchange reactions of amines. Murahashi, S., et al., J. Am. Chem. Soc., 105, 5002 (1983).
Among other things, imines made according to Applicants' invention are beneficial intermediates and precursors. For instance, certain free aldehydes are known to be unstable and reactive. By way of illustration, 3-pyridinecarboxaldehyde oxidizes to give the solid carboxylic acid, i.e., niacin, upon exposure to ambient conditions. The solidification indicates a chemical change which makes the substance useless to its intended purpose. As a consequence, aldehydes of this sort are difficult to handle. Often referred to as masked aldehydes, imines can be hydrolyzed through nucleophilic attack to the corresponding aldehyde. This property of imines makes them ideal aldehyde precursors which may be stored until the aldehyde is needed. At that time, the imine is hydrolyzed to form the aldehyde. However, this same property has in the past caused some difficulties in imine synthesis. Under synthesis conditions, the imine may tend to hydrolyze to the aldehyde so that relatively little imine product is obtained.
Applicants have also discovered that yields of desired unsymmetrical secondary amines from nitrile hydrogenations are unexpectedly improved appreciably when stable imine intermediates are used according to the present invention. Nitrile hydrogenations are known to result in the production of symmetrical secondary amines. Schwoegler, E. J. and Adkins, H., J. Am. Chem. Soc., 61, 3499 (1939) taught that the ratio of primary to secondary amines in nitrile hydrogenations is seldom greater than 3 to 1. These researchers also taught that the yield of primary amine can be increased through addition of ammonia. When amines are added to the nitrile hydrogenation mixture, mixed secordary amines are produced in various amounts since the partially hydrogenated nitrile and the added amine compete to combine into secondary products. Accordingly, the mixed secondary amines which form detract from the yield of desired unsymmetrical product. The effect of this decrease in yield is especially great when the reactants are expensive.
Applicants' invention overcomes the problem of interfering mixed secondary amine by-products in the synthesis of unsymmetrical secondary amines. An intermediate imine made according to Applicants' process can be isolated and then manipulated using transimination techniques to displace one group of the imine with a more preferred group. The resulting imine may then be further hydrogenated to yield the selected unsymmetrical secondary amine in surprisingly good yield. Applicants are unaware of any reported reaction processes for the production of unsymmetrical secondary amines utilizing stable imine intermediates and subjecting such intermediates to transimination prior to final hydrogenation.
In addition to the selectivity with which unsymmetrical amine products can be made, enhanced efficiency and cost effectiveness are possible. In the typically less quantitative imine synthesis step of the reaction, a cheaper or more abundant or available primary amine reactant may be used to react with the nitrile. The amine used for the transimination step might then be more costly, less readily available, etc. Valuable resources are consequently conserved.
Another aspect of Applicants' invention is the discovery that a very useful class of unsymmetrical secondary amines represented by the formula RCH.sub.2 NHAr (in which Ar is not attached to R) can be synthesized by the processes herein disclosed that utilize the reductive intermolecular coupling of non-aliphatic nitriles and primary aromatic amines. This class of unsymmetrical secondary amines has heretofore been accessible only with some difficulty.
Secondary amines of the general formula RCH.sub.2 NHAr, as well as imines of the general formula RCH.dbd.NHAr, are known to be useful, for example, in the synthesis of agricultural chemicals, such as the fungicides described in U.S. Pat. No. 4,358,446, "Use as Fungicides of N-(3-Pyridylmethyl)-N-acyl Anilines," issued to Ten Haken et al. in 1982. Ten Haken et al. teach that imines can be produced by coupling carbonyl pyridine compounds and amines with the loss of water.
The reductive intermolecular coupling of nitriles and primary aliphatic amines in molar ratios of about 1:1 is generally known to give unsymmetrical secondary amines, according to the following general reaction: EQU RCN+R'NH.sub.2 +H.sub.2 .fwdarw.RCH.sub.2 NHR'+RCH.sub.2 NH.sub.2.
These reductive couplings are known to take place between certain classes of nitriles and certain classes of amines. Applicants are unaware, however, of any instance where non-aliphatic nitriles have been reported to reductively couple with aromatic amines forming an unsymmetrical secondary amine product.
For example, in U.S. Pat. No. 2,798,077, "Preparation of Methyl-(beta-picolyl)-Amine," issued to R. Schlapfer et al. in 1957, it is disclosed that 3-cyanopyridine can be hydrogenated in the presence of excess methylamine and a Raney nickel catalyst to yield N-methyl-3-picolylamine and beta-picolylamine. Separation of the beta-picolylamine is then required.
Aromatic amines that also contain nitrile groups have been reported to cyclize during intramolecular nitrile reduction to synthesize bicyclic systems, such as indoles. Rylander, P. N., Catalytic Hydrogenation Over Platinum Metals, p.215 (Academic Press, 1967).
Kindler, K. and Hesse, F., Arch. Pharm., 271, 439 (1933) disclosed the synthesis of secondary and tertiary amines by the hydrogenation of nitriles. Primary and secondary aliphatic amines were added to the reaction mixture to yield various amine products. An intermediate aldime was proposed to explain the variety of products obtained.
Aliphatic nitriles have been shown to reductively couple with aromatic and aliphatic amines. U.S. Pat. No. 3,209,029 issued to Abramo et al. in 1965 discloses the synthesis of aminoalkyl-aromatic-ethylamines by the reduction of cyano-alkyl-aromatic-acetonitriles in the presence of a primary amine.
Further, certain catalysts are known to favor certain amine products in the hydrogenation of nitriles. In the hydrogenation of basic nitriles, including 3-cyanopyridine, to primary amines, formation of secondary symmetrical amine has been prevented by the use of a Raney nickel catalyst and the presence of ammonia. Various other catalysts including palladium and platinum catalysts, were reported to favor the formation of secondary amines. Huber, W., J. Am. Chem. Soc., 66, 876 (1944).
Rylander and Hasbrouck have discussed catalyst selectivity for certain amine products in the reductive coupling of benzonitrile and of aliphatic nitriles in the presence of aliphatic amines. Rhodium on carbon, palladium on carbon and platinum on carbon were investigated for amine selectivity. Palladium was generally found to be a poor catalyst for reductive couplings to form amines, while rhodium and platinum were selective for certain secondary amines.
The reductive intermolecular coupling of aromatic or heteroaromatic nitriles and aromatic primary amines to yield unsymmetrical secondary amines has, however, remained unknown. In fact, Juday and Adkins reported that aniline did not couple with nitriles under conditions that were effective for coupling aliphatic amines with nitriles. Juday, R. E. and Adkins, H., J. Am. Chem. Soc., 77, 4559 (1955). In other work, Juday reported that no mixed secondary amine product formed from the addition of primary amines to the hydrogenation mixture of aromatic nitriles. The yield of tetrahydrohydrobenzamide did, however, increase. Juday, R. E., Proc. Montana Acad. Sci., 7-8, 84 (1947-48).